In general, there are two synthetic approaches concerning preparation of solifenacin, either as a racemic mixture or biologically active pure isomer (1S, 3′R). One of them is based on the reaction of quinuclidinol and 1-phenyl-1,2,3,4-tetrahydroisoquinoline carbamoyl derivative with good leaving group. Another approach regards the condensation of 1-phenyl-1,2,3,4-tetrahydroisoquinoline and active quinuclidinol derivative, such as chloroformate or carbonate for instance. In EP 0801067 B1 and WO 2005/105795 chloride, lower alkoxides and phenoxide groups as well as 1H-imidazol-1-yl, 2,5-dioxopyrrolidin-1-yloxyl and 3-methyl-1H-imidazol-3-ium-1-yl were mentioned as good leaving groups in this process.
In European patent EP 0801067 B 1, transesteryfication of carbamoyl ethyl ester derivative of 1-phenyl-1,2,3,4-tetrahydroisoquinoline racemic mixture proceeded in toluene suspension in the presence of sodium hydride; obtained diastereoisomeric mixture of products was resolved due to chiral high-pressure liquid chromatography technique.
In J. Med Chem., 2005, 48 (21), 6597-6606, instead of the racemic mixture, ethyl (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate as pure enantiomer was used. This optically active semiproduct was obtained in the prior step, in the reaction of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline and ethyl chloroformate in the presence of potassium carbonate.
The above mentioned methods require use of sodium hydride as well as expensive, optically active (R)-quinuclidinol in big excess. In addition, this reaction proceeds in moderate yield about 50%, that makes the process not suitable in an industrial scale manufacturing process.
In EP 0801067 B1, the possibility of solifenacin preparation in the condensation reaction of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carbamoyl chloride and (R)-3-quinuclidinol was also mentioned, however none preparative example of this process was given.
Synthetic route of solifenacin disclosed in WO 2005/105795 comprises the reaction of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinolinecarbonyl chloride and (R)-quinuclidinol in the presence of base. In the example, (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline is treated with phosgene in toluene in the presence of triethylamine. After addition of methanol and water to the reaction mixture, followed by evaporation of organic solvents, the reaction product is being isolated as an oil. The obtained intermediate in toluene solution is then added to the mixture of (R)-3-quinuclidinol and sodium hydride in toluene at reflux. The reaction is carried out under the same conditions overnight. Authors of this publication claimed that, ‘solifenacin formation had been confirmed’, but neither yield nor purity of thus obtained product was revealed. Following thereinbefore procedure, the present Inventors obtained solifenacin of purity less than 43% according to HPLC analysis.
The route of synthesis comprising the reaction of 1-phenyl-1,2,3,4-tetrahydroisoquinoline and 3-quinuclidinol in dimethylformamide, described in EP 0801067, was reproduced in WO 2007/147374. The formation of substantial amount of symmetrically disubstituted urea derivative was observed which significantly reduced the yield of the main product. This by-product formation was ascribed to the acylation at 3-quinuclidinol nitrogen atom giving a quaternary ammonium salt, the salt hydrolysis with further decarboxylation of the formed acid, followed by the reaction of the thus obtained 1-phenyl-1,2,3,4-tetrahydroisoquinoline with the residue of the acylation agent.
Except for detailed considerations of the reaction mechanism, we established, the uretane by-product with two chiral carbon atoms is obtained under very similar conditions also in case the optically active reagents are used. On account of low solubility in organic solvents, this disubstituted uretane derivative is difficult to get rid off the final product, using standard purification methods, for example, crystallization. Therefore, to obtain solifenacin of pharmaceutical purity, the formation of urethane by-product should be significantly diminished prior to converting solifenacin into its pharmaceutically acceptable salt.
The pharmaceutical substances authorized for human use must meet the requirements established by International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). These standards impose the necessity to develop new, more effective methods of solifenacin and the salts thereof synthesis, in comparison to the processes known in the prior art. Whenever hereafter a reference is made to ‘solifenacin of pharmaceutical purity’, is to be understood solifenacin or its salts with pharmaceutically acceptable acids, including less than 0,1% of single impurities or less than 0,4% of unidentified impurities in total.
Attempts made to obtain solifenacin of pharmaceutical purity in the reaction of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinolinecarbonyl chloride and (R)-quinuclidinol proved, that purity of the final product strongly depends on the purity of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinolinecarbonyl chloride used in this reaction. It is generally known that (S)-1-phenyl-1,2,3,4-tetrahydroisoquinolinecarbonyl chloride may be synthesized from chiral 1-(S)-phenyl-1,2,3,4-tetrahydroisoquinoline upon treatment with carbonylating reagent, such as gaseous carbon oxychloride (phosgene), liquid trichloromethyl chloroformate (diphosgene), solid bis-(trichloromethyl) carbonate (triphosgene), urea and other. Some impurities accompanying (S)-1-phenyl-1,2,3,4-tetrahydroisoquinolinecarbonyl chloride, especially the residues of unreacted 1-(S)-phenyl-1,2,3,4-tetrahydroisoquinoline impede purification of solifenacin. On account of similar polarity of 1-(S)-phenyl-1,2,3,4-tetrahydroisoquinoline and solifenacin base, the succinate salt of the former co-crystallizes with the final solifenacin succinate. As it was said before, 1-(S)-phenyl-1,2,3,4-tetrahydroisoquinoline reacts with solifenacin obtained in the next step, thereupon undesired uretane by-product is formed.